ES2239648T3 - PHARMACEUTICAL COMPOSITIONS OF AN NMDA RECEIVER AGONIST. - Google Patents

Abstract

A pharmaceutical composition comprising a pharmaceutically effective amount of (1S, 2S) -1- (4- hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof and water, said composition containing less than about 2 parts per million free copper ions and less than about 2 parts per million free iron ions.

Description

Pharmaceutical compositions of an agonist from NMDA receptor.

Background of the invention

This invention provides compositions stable pharmaceuticals of an acid receptor antagonist N-methyl-D-aspartic (NMDA), (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol, procedures for the preparation of such compositions Pharmaceuticals and procedures to treat stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, degenerative diseases of the CNS such as Alzheimer's disease, senile dementia of Alzheimer's type, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychotic conditions, drug addictions, migraine, hypoglycemia, anxiety states, urinary incontinence and events ischemic produced by a surgical operation in the CNS, by open heart surgery or by any procedure during which is compromised the function of the cardiovascular system, which use the pharmaceutical compositions of this invention.

He (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol (hereinafter referred to as "Compound") is an agent neuroprotector that is useful for the treatment of stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, degenerative diseases of the CNS such as Alzheimer's disease, senile dementia of Alzheimer's type, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychotic conditions, drug addictions, migraine, hypoglycemia, anxiety states, urinary incontinence and events ischemic produced by a surgical operation in the CNS, by open heart surgery or by any procedure during which is compromised the function of the cardiovascular system. He Compound exhibits activity as an NMDA receptor antagonist. NMDA is an excitatory amino acid involved in neurotransmission exciter in the central nervous system. NMDA antagonists they are compounds that block the NMDA receptor by means of interaction with the receptor binding site.

The neurotransmission antagonists in the NMDA receptors are useful therapeutic agents for Neurological disorders treatment. United States Patent No. 4,902,695 refers to a series of NMDA antagonists competitive useful for the treatment of neurological disorders, including epilepsy, stroke, anxiety, cerebral ischemia, muscle spasms and neurodegenerative disorders such as Alzheimer's disease and Huntington's disease. The patent of United States No. 4,968,878 refers to a second series of competitive NMDA receptor antagonists useful for treatment of neurological disorders and disorders Similar neurodegenerative United States Patent No. 5,192,751 describes a procedure for treating the urinary incontinence in a mammal, which comprises administering a effective amount of a competitive NMDA antagonist.

U.S. Patent No. 5,272,160 assigned legally and U.S. Patent No. 5,710,168 assigned legally (whose descriptions are incorporated in this document as reference) describe the Compound and the procedures for using the Compound for the treatment of diseases or conditions that are susceptible to treatment by blocking sites NMDA receptors, including stroke, trauma to the spinal cord, traumatic brain injury, dementia multi-infarction, degenerative CNS diseases, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychotic conditions, drug addictions, migraine, hypoglycemia, anxiety states, urinary incontinence and events ischemic

U.S. Patent No. 6,008,233 assigned legally (whose description is incorporated in this document as reference), describes the methanesulfonate trihydrate of Compound and uses of it for the treatment of diseases and conditions mentioned above.

The Compound is preferably administered as an intravenous infusion that lasts many hours. Such administration aims to maintain a desired level of the compound in blood for All therapy Typically, Compound therapy is initiated. in the emergency room of a hospital and continues for a period of desired time in the ICU or in another care unit critics

The formulations and presentations of Compound dosing should be designed for administration convenient and effective and should be especially suitable for urgent situations. In such formulations, it must be Compound degradation minimized.

Summary of the Invention

This invention provides formulations relatively stable of the Compound in aqueous solutions, obtained by reduction or elimination of the presence of ions Metallic traces in the solutions. Stability is improved additionally by means of the use of a buffer pharmaceutically acceptable. Additional stability is achieved by reducing the presence of oxygen in the formulations.

One aspect of the present invention relates to pharmaceutical compositions comprising an amount pharmaceutically effective of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof and water, containing said compositions less than about 2 parts per million free copper ions and less than about 2 parts per million of free iron ions.

Another aspect of the present invention relates to to pharmaceutical compositions comprising (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof, water and an agent pharmaceutically acceptable chelator, preferably acidic ethylenediaminetetraacetic acid, citric acid, succinic acid or acid tartaric, or a pharmaceutically acceptable salt thereof, at a effective concentration to form chelates with metal ions trace present in said composition.

Another aspect of the present invention relates to to pharmaceutical compositions comprising (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof in a solution aqueous, in which the percentage of the degradation product, 4-hydroxybenzaldehyde, does not constitute more than approximately 0.15 percent of said composition after storage at 50 ° C for 12 weeks, preferably not constitutes more than about 0.07 percent and more preferably it does not constitute more than about 0.04 per percent under the conditions mentioned.

A further aspect of this invention relates to to pharmaceutical compositions comprising (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof in a solution aqueous, in which the percentage of the degradation product, 4-hydroxy-4-phenylpiperidine, does not constitute more than approximately 0.2 percent of said composition after storage at 50 ° C for 12 weeks, preferably it does not constitute more than about 0.1 per hundred and more preferably does not constitute more than about a 0.05 percent under the conditions mentioned.

Another additional aspect of this invention is refers to procedures to treat stroke, trauma of spinal cord, traumatic brain injury, dementia multi-infarction, degenerative diseases of the CNS such as Alzheimer's disease, senile type dementia Alzheimer's, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychotic conditions, drug addictions, migraine, hypoglycemia, anxiety states, urinary incontinence and events ischemic produced by a surgical operation in the CNS, by open heart surgery or by any procedure during which is compromised the function of the cardiovascular system, in mammals, which comprise administering to the mammal in need of such treatment a pharmaceutical composition of this invention.

In a preferred embodiment of the aspects of the composition of this invention, the compositions lack substantially free copper ions and iron ions free.

In another preferred embodiment of the aspects of the composition of this invention, the compositions contain less of about 2 parts per million of any metal ion free trace, and more preferably they lack substantially any free trace metal ion.

Another preferred embodiment of the aspects of the composition of this invention stipulates that the compositions comprise a pharmaceutically acceptable buffer at a concentration effective to maintain the pH of the compositions at a value between about 3.8 and about 5.0 and, more preferably, at a value between about 4.0 and approximately 4.5. In a more preferred embodiment, the anion of the buffer is selected from acetate, citrate, tartrate, formate and lactate, more preferably lactate.

Another preferred embodiment of the aspects of the Composition of this invention stipulates that the compositions lack substantially oxygen.

In a preferred embodiment of the process of The treatment aspects of this invention, the mammal is a being human.

The term "chelating agent", as used herein, refers to any compound that sequesters, forms a complex or otherwise interacts with trace metal ions in such a way as to minimize the destabilizing effect of the Compound in aqueous solution by such metal ions Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts, trans-1,2-diaminocyclohexanetratraacetic acid (DCTA) and its salts, bis- (2-aminoethyl) ethylene glycol-N, N , N ', N'-tetraacetic acid (EGTA) and its salts, diethylenetriaminepentaacetic acid (DTPA) and its salts, tri- (2-aminoethyl) amine (train), N, N, N', N ' -tetra- (2-aminoethyl) ethylenediamine (penten), nitrilotriacetic acid (NTA) and its salts, 2,3-dimercapto-1-propanesulfonic acid (DMPS) and its salts, meso-2,3-dimercaptosuccinic acid (DMSA) and its salts, hydroxy acids such as citric, tartaric, lactic, succinic acid, etc. and its salts, and certain amino acids such as glycine, histidine and glutamic acid, and their
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The expression "Degradation Product 1", as used herein, refers to the degradation product of the Compound, 4-hydroxybenzaldehyde.

The expression "Degradation Product 2", as used herein, refers to the degradation product of the Compound, 4-hydroxy-4-phenylpiperidine.

The expressions "free copper ion", "ion of free iron "e" free trace metal ion ", as used in this document, they refer to copper ions, iron ions or trace metal ions, respectively, that when present in an aqueous composition comprising the Compound, they are in a form or state that allows them to cause, initiate, induce or catalyze Compound degradation.

"Upper space" refers to the difference in volume between the volume of a closed container (for example, one vial) and the volume of liquid contained in that container. The upper space can be quantified as a percentage of the total volume of the closed container.

The expression "means to eliminate ions trace metals ", as used herein, refers to any means that can be used to remove metal ions trace of an aqueous solution. For example, such means can include the use of metal chelating resins or other reagents Chelators known to those skilled in the art.

The expression "non-reactive gas", as used in this document, refers to any gas that does not react or interact chemically with a pharmaceutical composition or Any of its components. Such gas is preferably nitrogen, but it can be argon, helium or any other gas known to Specialists in the art for their non-reactive properties.

The expressions "Product percentage of Degradation 1 "and" percentage of Degradation Product 2 " refer to the percentage of the applicable degradation product present in a pharmaceutical composition of the Compound, by weight (p / p). The percentage is calculated from the areas under the peaks obtained by HPLC analysis according to the formula:

% Of Degradation Product = [(A_ {SAMP} x D_ {SAMP}) / (R_ {AVG} x C_ {LAB})] x 100

in the that:

A_ {SAMP} = area under the peak of impurities

D_ {SAMP} = dilution factor, calculated as:

D_ {SAMP} = C_ {LAB} / C_ {SAMP}

where:

C_ {LAB} = concentration, indicated on the label, of the Compound in the formulation to be tested (base concentration free)

C_ {SAMP} = concentration of the free base of the Compound in the sample tested (based on the dilution of the concentration indicated on the label used to get the sample)

R_ {AVG} = en the mean standard response factor ("R") obtained from analysis of a standard solution, calculated as:

R = A_ {STD} / (C_ {STD} x PF)

where:

A_ {STD} = area under the peak of the Compound in the standard solution

C_ {STD} = Concentration of the Compound in the standard solution

PF = factor of Potency of the Compound in the standard solution, calculated as the weight molar of the free base of the compound divided by the molar weight of the real compound in the standard solution.

The dilution factor, D_ {SAMP}, represents the dilution that may be necessary for the tested sample to be within the validated concentration limits of the procedure HPLC

The expression "pharmaceutically acceptable", As used herein, it refers to vehicles, diluents, excipients, buffers and / or salts that are compatible with others formulation ingredients and not harmful to the recipient thereof.

The expression "substantially without", as used in this document regarding the presence of metal ions trace in the pharmaceutical compositions comprising the Compound, refers to an amount that is less than what it would have a substantial effect on the degradation of the Compound in such compositions Despite the above, such amount is less than approximately 2 ppm for any applicable trace metal ion. The expression "substantially without", as used herein document regarding the presence of oxygen in or in contact with the pharmaceutical compositions comprising the compound, refers to an amount of oxygen that is less than what an substantial effect on the degradation of the Compound in such compositions For example, in compositions packaged in closed containers or vials that have an upper space that is 25% or less of the volume of the container or vial, the expression "substantially without" means that there is less than 10% of oxygen in such upper space.

The term "trace metal ion", as used in this document, refers to any metal ion that, when It is present in an aqueous pharmaceutical composition comprising the Compound, cause, initiate, induce or catalyze the degradation of the Compound, especially transition metal ions and, more especially, iron and copper ions.

Detailed description of the invention

In the present pharmaceutical compositions, the active ingredient is (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol, which may be present in the form of its free base or as a salt pharmaceutically acceptable, preferably the methanesulfonate salt (mesylate). The preparation of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol it is described in US Patent No. 5,272,160 and in the U.S. Patent No. 6,008,233. Salt preparation mesylate trihydrate is described in US Patent No. 6,008,233.

In a representative example, the (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol it is given to a patient with a stroke or trauma cranial in an emergency room or in the emergency room of a hospital through intravenous infusion. Therapy should continue in the ICU or other critical care units. The amount of compound to be administered must depend, in part, on the patient body weight.

A concentrated solution of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol which can be easily diluted according to the needs of the patient, provides the required dosage flexibility. Yes if necessary, the concentrated solution can be diluted to the appropriate concentration for patient administration.

The formulations of the present compositions pharmaceuticals may be in the form of concentrated solutions intended to be diluted in a suitable IV diluent before administration. Formulations can also be prepared as ready-to-use forms that are at concentrations that can administered without further dilution. The preferred concentration of the compositions in concentrated form is 10 milligrams of the free base of the active compound, (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol, per milliliter of solution (i.e. 10 mgA / ml). Concentration Preferred of the ready-to-use forms is 1.25 mgA / ml.

The composition is administered with its potency complete or diluted when necessary. A concentration of Preferred dosage for administration to the patient is 0.1 mgA / ml to 10 mgA / ml. A more preferred dose for administration It is a concentration of 0.5 mgA / ml to 2.0 mgA / ml. A concentration Even more preferred dosage is 1.25 mgA / ml. Thinner Preferred IV of the composition is normal saline (NaCl at 0.9%).

The two degradation products produced by chemical degradation of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol in aqueous solutions are the compounds 4-hydroxybenzaldehyde (hereinafter referred to as "Degradation Product 1") and 4-hydroxy-4-phenylpiperidine (hereinafter referred to as "Degradation Product 2"). Though The following theory is not essential for the practice of this invention and is not intended to limit it in any way, it is believed that such degradation is the result of oxidation of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol.

It has been discovered that ion contamination trace metals is a critical factor for the degradation of Compound. Such effects are illustrated by experiments of known additions to solutions containing the Compound with iron or copper ions. Table 1 shows the effect of the iron and copper ions in a non-buffered water solution for injection (WFI) on the formation of the products of degradation.

TABLE 1 Effect of the addition of known amounts of Fe 2+ and Cu 2+ on the degradation of the Compound. The numbers represent the percentage of the Degradation Product 1 (p / p)

one

       \ dotable {\ tabskip \ tabcolsep # \ hfil \ + # \ hfil \ tabskip0ptplus1fil \ dddarstrut \ cr} {
 \ + \ begin {minipage} {145mm} WFI = water for injection. TO
Chelex® treated solutions containing 1.25 mgA / ml of
Compound, 20 ppm of iron or copper was added and then
sterilized in an autoclave at 121 ° C for 8
minutes. \ end {minipage} \ cr}
    

An effective means to improve stability Compound chemistry is achieved by eliminating trace metal ions of the aqueous formulation. An ion removal procedure Metallic is through the use of designed agents specifically for this purpose. The illustrative agents for remove metal ions include chelating resins such as Chelex® (Chelex is a trademark of Bio-Rad Laboratories, Inc., Hercules, CA). However, they can be other pharmaceutically acceptable chelating resins or reagents acceptable to perform the same function, provided they do not affect detrimentally to the Compound or the other components of the formulation.

The ion removal treatment trace metals can be performed on individual components of the formulation before the final formulation or such treatment can be done on the formulation itself. For example, the water that is will be used in the formulation can be treated to remove metals trace Alternatively, concentrated buffer solutions can be treated before dilution with water and formulation with the active ingredient. In another alternative, the aqueous solution that It contains all the components of the formulation except the Active pharmaceutical ingredient can be treated to eliminate metal ions Another additional alternative is to treat the formulation complete that contains all the components, including the active ingredient.

An alternative to eliminate metal ions trace is to incorporate certain compounds into the formulation that they will form a chelate with trace metal ions, minimizing This way its degradation effect. Examples of such agents chelants include disodium ethylenediaminetetraacetic acid (EDTA) and citrate and tartrate buffers. The preferred concentration of EDTA Disodium, citrate buffer and tartrate buffer is 10 mM each. Be believes that citrate and tartrate act as chelating agents for The metal ions trace. In addition, it is believed that succinate acts As a chelating agent. Other chelating agents will be apparent for those skilled in the art in light of this description.

The aqueous solutions of the Compound are susceptible to change of pH. It is believed that the compound presents its better chemical stability at a pH between 4.0 and 4.5. When the Compound is formulated only with water, the pH of the formulation increases above 5. This pH change produces favorable conditions for the oxidative degradation reaction, accelerating in this way the degradation of the aqueous formulation. The increase in pH also reduces the solubility of the compound, thus increasing the possibility of precipitation in the solution.

The pH change can be minimized using a adequate buffer. Those skilled in the art will appreciate that any pharmaceutically acceptable buffer that can be used Maintain the pH of the formulation within a certain range. He pH range of such buffer is preferably between about 3.8 and about 5.0, and more preferably between 4.0 and 4.5. Suitable buffers include, but without limitation, buffers acetate, benzoate, citrate, formate, lactate and tartrate, preferably lactate.

Table 2 exemplifies the use of various buffers to stabilize the pH of formulations containing 10 mgA / ml of the Compound.

TABLE 2 pH at 70 ° C

2

To further improve the stability of the active compound, it is preferable to reduce the oxygen content of the formulation This can be done by spraying the solution formulation with nitrogen, argon or other non-reactive gas, when Compositions of the invention are packaged in vials or containers similar containing a higher space, using such gases inert to the upper space. When the compositions of the invention are packaged so that they contain a superior space, it is it is preferable that the oxygen content of the upper space is less than about 12% and, more preferably, less than approximately 8%. Oxygen can be removed by others procedures, including the use of vacuum to remove air and oxygen. Other specialists in the art will be apparent. Oxygen removal procedures.

A preferred presentation of aspects of the Composition of the invention comprises the Compound at a concentration of 10 mgA / ml. This concentration is close to the Maximum solubility of the Compound (approximately 12 mgA / ml at 5 ° C). The preferred solution of the composition is 10 mM lactate buffer. Without However, those skilled in the art will appreciate that they can buffer solutions of other anions are used, including, but not limitation, buffer solutions of the anions acetate, citrate, Tartrate and formate.

A preferred container of the compositions is a Type I Flint molded glass vial of 40 cc, with a stopper rubber and aluminum wrap. The alternative presentations may include other vials or types of containers, syringes pre-loaded or IV bags pre-loaded Other packaging presentations will be evident to those skilled in the art.

The vials are preferably sterilized by Final sterilization procedures using an autoclave. Preferably, sterilization is performed for 8 minutes at 121 ° C. Sterilization can cause a slight change in pH. In the formulation buffered with lactate, the pH is reduced slightly. For achieve a midpoint in the preferred pH range, the pH Initial preferably set to 4.5. The sterilization cycle final reduces the pH to approximately 4.2.

Experimental examples

The present invention is illustrated by means of following examples, although not limited to the details of same.

Percentages of Degradation Product 1 and Degradation Product 2 measured using phase HPLC analysis inverse on a Kromasil® C4, 5 µm, 25 cm column Length x 4.6 mm ID (EKA Chemicals, Bohus Sweden). The column temperature was 30 ° C ± 5 ° C. Mobile phase A: water / acetonitrile / trifluoroacetic acid, 90/10 / 0.1 (v / v / v). Phase mobile B: water / acetonitrile / trifluoroacetic acid, 40/60 / 0.1 (v / v / v). Gradient profile: linear. Detection: UV @ 215 nm. Flow rate: 1.5 ml / min. Injection volume: 10 µl.

Example 1 Effect of treatment with a chelating resin

Sodium chloride solutions of 0.3 were treated, 0.6 and 0.9% with 5% w / w Chelex® resin and slowly stirred for 1 hour. The pH of the solutions was adjusted to 4.6 while stirred with Chelex resin. The mixture was then filtered. Be prepared control samples of sodium chloride solutions 0.3, 0.6 and 0.9% that were not treated with Chelex resin. The treated and untreated solutions were combined with (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol at a concentration of 1.25 mgA / ml and stored in vials Hermetically sealed 5cc Flint type I molded contained 4.0 ml of solution and an upper air gap of 2.0 ml, at 70 ° C for 7 days. The results of this experiment are they represent in Table 3.

TABLE 3 The numbers represent the percentage of the Product of Degradation 1 (p / p)

3

Example 2 Effect of the formulation with a chelating agent

The following solutions were prepared at a concentration of 10 mM each, at a pH of 4.2:

1. Normal unbuffered saline solution (NaCl at 0.9%);

2. 10 mM citrate buffer in normal saline (0.9% NaCl);

3. 10 mM tartrate buffer in saline solution normal (0.9% NaCl); Y

4. 10 mM disodium EDTA in normal saline (0.9% NaCl);

The solutions of each case were combined with (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol at a concentration of 1.25 mgA / ml and the pH was adjusted to 4.2. Every formulation was subjected to an autoclave cycle of 8 minutes at 121 ° C and then stored at 70 ° C. The results of this experiment are they represent in Table 4 shown below.

TABLE 4 The numbers represent the percentage of the Product of Degradation 1 (p / p)

4

Example 3 4-Hydroxybenzaldehyde (Degradation Product one)

An NMR analysis was performed at temperature ambient on a Bruker Advance DRX 500 MHz NMR spectrometer using a 5 mm Bruker gradient broadband reverse probe (Bruker Instruments, Inc., Billerica, MA). The sample dissolved in 99.9% deuterated dimethylsulfoxide (DMSO).

5

Example 4 4-Hydroxy-4-phenylpiperidine (Degradation Product 2)

An NMR analysis was performed at temperature ambient on a Bruker Advance DRX 500 MHz NMR spectrometer using a 5 mm Bruker gradient broadband reverse probe. The sample was dissolved in dimethylsulfoxide (DMSO) deuterated at 99.9%

6

Example 5 Formulation of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol in lactate buffer

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7

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The pH of the initial formulation was set to pH 4.5 to adjust the slight reduction in pH after sterilization final. The final sterilization cycle reduces the pH to approximately 4.2. When necessary, sodium hydroxide and hydrochloric acid to adjust the solution to the desired pH.

Example 6 Accelerated Stability Study

A solution of 10 mgA / ml of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol in 10 mM lactate buffer. The pH of three separate portions was adjusted so that the initial pH after final sterilization was of 3.9, 4.2 or 4.6. The formulation was packaged in vials containing various concentrations of oxygen or in air. Sterilization final was performed by means of an autoclave at 121 ° C for 8 minutes The samples were stored in Flint vials of type I of 40 ml with 40 ml load and 10 ml of upper space for 12 weeks at 30 ° C, 40 ° C and 50 ° C.

The results of this experiment are presented in Table 5 and in Table 6 shown below.

TABLE 5 The numbers represent the percentage of the Product of Degradation 1 (p / p)

9

TABLE 6 The numbers represent the percentage of the Product of Degradation 2 (p / p)

10

Claims (15)

1. A pharmaceutical composition comprising a pharmaceutically effective amount of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof and water, containing said composition less than about 2 parts per million of free copper ions and less than about 2 parts per million of free iron ions. 2. A pharmaceutical composition of the claim 1, substantially lacking said composition of free copper ions and free iron ions. 3. A composition of claim 1, said composition containing less than about 2 parts per million of any free trace metal ion. 4. A pharmaceutical composition of the claim 3, substantially lacking said composition of any free trace metal ion. 5. A pharmaceutical composition comprising (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof, water and an agent Pharmaceutically acceptable chelator, at an effective concentration to form chelates with trace metal ions present in said composition. 6. A pharmaceutical composition of the claim 5, wherein said chelating agent is selected between ethylenediaminetetraacetic acid, citric acid, acid succinic and tartaric acid, and pharmaceutically acceptable salts of the same. 7. A pharmaceutical composition of claims 1-6, further comprising a buffer pharmaceutically acceptable at an effective concentration to maintain the pH of the composition at a value between about 3.8 and about 5.0. 8. A pharmaceutical composition of the claim 7, wherein the buffer is at a concentration effective to maintain the pH of the composition at an included value between about 4.0 and about 4.5. 9. A pharmaceutical composition of the claim 7 or 8, wherein the anion of said buffer is Select between acetate, citrate, tartrate, formate and lactate. 10. A pharmaceutical composition of the claim 9, wherein the anion of said buffer is lactate. 11. A pharmaceutical composition of claims 1-10, substantially lacking said oxygen composition. 12. A pharmaceutical composition comprising (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof in a solution aqueous, in which the percentage of the degradation product 4-hydroxybenzaldehyde is not greater than about 0.15 percent of said composition after storage at 50 ° C for 12 weeks. 13. A pharmaceutical composition of the claim 12, wherein the percentage of said product of degradation is not greater than about 0.07 percent. 14. The pharmaceutical composition of the claim 13, wherein the percentage of said product of degradation is not greater than about 0.04 percent. 15. Use of a pharmaceutical composition of claims 1-14 for the manufacture of a medication for the treatment of stroke, trauma of the spinal cord, traumatic brain injury, dementia multi-infarction, degenerative diseases of the CNS such as Alzheimer's disease, senile type dementia Alzheimer's, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychotic conditions, drug addictions, migraine, hypoglycemia, anxiety states, urinary incontinence and events ischemic produced by a surgical operation in the CNS, by open heart surgery or by any procedure during which is compromised the function of the cardiovascular system, in a mammal.